Landscape of cancer clinical trials in India - a comprehensive analysis of the Clinical Trial Registry-India.

Background: Cancer is one of the leading causes of morbidity and mortality in India. Clinical trials are critical for driving innovation in cancer therapy, diagnosis, and prevention. This study aims to depict the evolving landscape of cancer clinical trials in India by analysing the clinical trials registered in Clinical Trial Registry-India (CTRI). Methods: We identified cancer trials registered in CTRI (between 2007 and 2021) using search terms adapted from the cancer types defined by the National Cancer Institute (USA). We then collated and analysed the publicly available information from CTRI (cancer subtypes, type of trial, treatment intent, type of intervention, sponsor type, recruitment countries) and used descriptive statistics to illustrate the overall as well as year-to-year trend. Findings: In total, we identified 1988 cancer trials, the majority of which focused on treating cancer (63%) and rest of the trials aimed at optimising the operational aspects of surgery (19%), mitigating treatment-related toxicity (10.6%), or treating cancer-related symptoms (7.8%). Focusing on trials with the intent of treating cancer, we found that most were investigating solid tumours as opposed to haematological malignancies with the most prominent cancer subtypes being breast cancer (17%), head and neck cancer (9.8%), lung cancer (9.6%), and cervical cancer (6.6%). The number of trials conducted in a given cancer subtype from our analysis overall correlated to the incidence, mortality, and 5-year prevalence of the respective cancer subtype in India; however, head and neck cancer and cervical cancer were underrepresented in trials as compared with the disease burden. The most common type of intervention was investigational drugs. The most common sponsor types were global pharmaceutical industry (26%) and research institution and hospital (26%). Despite a relatively high cancer burden, the availability of cancer trials in the Northeastern states of India was limited. Interpretation: There is a pressing need for clinical cancer research in India to be better aligned with the nation's healthcare needs and disease burden, focusing on prevalent and deadly cancers while ensuring the availability of clinical trials across geographic regions and underserved populations. Funding: Pi Health USA, a fully owned subsidiary of BeiGene Ltd.

Transitional dynamics in oncology clinical trials: evaluating the impact of Clinical Trials Act on cooperative groups.

OBJECTIVE: large-scale multicentre clinical trials conducted by cooperative groups have generated a lot of evidence to establish better standard treatments. The Clinical Trials Act was enforced on 1 April 2018, in Japan, and it has remarkably increased the operational burden on investigators, but its long-term impact on cancer cooperative groups is unknown. METHODS: a survey was conducted across the nine major cooperative groups that constitute the Japan Cancer Trials Network to assess the impact of Clinical Trials Act on the number of newly initiated trials from fiscal year (from 1 April to 31 March) 2017 to 2022 and that of ongoing trials on 1 April in each year from 2018 to 2023. RESULTS: the number of newly initiated trials dropped from 38 trials in fiscal year 2017 to 26 trials in fiscal year 2018, surged to 50 trials in fiscal year 2019, but then gradually decreased to 25 trials by fiscal year 2022. Specified clinical trials decreased from 32 trials in fiscal year 2019 to 12 trials in fiscal year 2022. The number of ongoing trials was 220 trials in 2018, peaked at 245 trials in 2020, but then gradually decreased to 219 trials by 2023. The number of specified clinical trials has been in consistent decline. By April 2023, of the 20 ongoing non-specified clinical trials, nine adhered to Clinical Trials Act and 11 followed the Ethical Guidelines for Medical and Health Research Involving Human Subjects. CONCLUSION: the number of multicentre clinical trials in oncology gradually decreased after the Clinical Trials Act's enforcement, which underscores the need for comprehensive amendment of the Clinical Trials Act to streamline the operational process.

An assessment of the informative value of data sharing statements in clinical trial registries.

BACKGROUND: The provision of data sharing statements (DSS) for clinical trials has been made mandatory by different stakeholders. DSS are a device to clarify whether there is intention to share individual participant data (IPD). What is missing is a detailed assessment of whether DSS are providing clear and understandable information about the conditions for data sharing of IPD for secondary use. METHODS: A random sample of 200 COVID-19 clinical trials with explicit DSS was drawn from the ECRIN clinical research metadata repository. The DSS were assessed and classified, by two experienced experts and one assessor with less experience in data sharing (DS), into different categories (unclear, no sharing, no plans, yes but vague, yes on request, yes with specified storage location, yes but with complex conditions). RESULTS: Between the two experts the agreement was moderate to substantial (kappa=0.62, 95% CI [0.55, 0.70]). Agreement considerably decreased when these experts were compared with a third person who was less experienced and trained in data sharing ("assessor") (kappa=0.33, 95% CI [0.25, 0.41]; 0.35, 95% CI [0.27, 0.43]). Between the two experts and under supervision of an independent moderator, a consensus was achieved for those cases, where both experts had disagreed, and the result was used as "gold standard" for further analysis. At least some degree of willingness of DS (data sharing) was expressed in 63.5% (127/200) cases. Of these cases, around one quarter (31/127) were vague statements of support for data sharing but without useful detail. In around half of the cases (60/127) it was stated that IPD could be obtained by request. Only in in slightly more than 10% of the cases (15/127) it was stated that the IPD would be transferred to a specific data repository. In the remaining cases (21/127), a more complex regime was described or referenced, which could not be allocated to one of the three previous groups. As a result of the consensus meetings, the classification system was updated. CONCLUSION: The study showed that the current DSS that imply possible data sharing are often not easy to interpret, even by relatively experienced staff. Machine based interpretation, which would be necessary for any practical application, is currently not possible. Machine learning and / or natural language processing techniques might improve machine actionability, but would represent a very substantial investment of research effort. The cheaper and easier option would be for data providers, data requestors, funders and platforms to adopt a clearer, more structured and more standardised approach to specifying, providing and collecting DSS. TRIAL REGISTRATION: The protocol for the study was pre-registered on ZENODO ( https://zenodo.org/record/7064624#.Y4DIAHbMJD8 ).

Both clinical trial register and electronic bibliographic database searches were needed to identify randomized clinical trials for systematic reviews: an evaluation study.

OBJECTIVES: To determine whether clinical trial register (CTR) searches can accurately identify a greater number of completed randomized clinical trials (RCTs) than electronic bibliographic database (EBD) searches for systematic reviews of interventions, and to quantify the number of eligible ongoing trials. STUDY DESIGN AND SETTING: We performed an evaluation study and based our search for RCTs on the eligibility criteria of a systematic review that focused on the underrepresentation of people with chronic kidney disease in cardiovascular RCTs. We conducted a combined search of ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform through the Cochrane Central Register of Controlled Trials to identify eligible RCTs registered up to June 1, 2023. We searched Cochrane Central Register of Controlled Trials, EMBASE, and MEDLINE for publications of eligible RCTs published up to June 5, 2023. Finally, we compared the search results to determine the extent to which the two sources identified the same RCTs. RESULTS: We included 92 completed RCTs. Of these, 81 had results available. Sixty-six completed RCTs with available results were identified by both sources (81% agreement [95% CI: 71-88]). We identified seven completed RCTs with results exclusively by CTR search (9% [95% CI: 4-17]) and eight exclusively by EBD search (10% [95% CI: 5-18]). Eleven RCTs were completed but lacked results (four identified by both sources (36% [95% CI: 15-65]), one exclusively by EBD search (9% [95% CI: 1-38]), and six exclusively by CTR search (55% [95% CI: 28-79])). Also, we identified 42 eligible ongoing RCTs: 16 by both sources (38% [95% CI: 25-53]) and 26 exclusively by CTR search (62% [95% CI: 47-75]). Lastly, we identified four RCTs of unknown status by both sources. CONCLUSION: CTR searches identify a greater number of completed RCTs than EBD searches. Both searches missed some included RCTs. Based on our case study, researchers (eg, information specialists, systematic reviewers) aiming to identify all available RCTs should continue to search both sources. Once the barriers to performing CTR searches alone are targeted, CTR searches may be a suitable alternative.

Cumulative live birth rate of in vitro fertilization cycle via progestin-primed ovarian stimulation versus gonadotropin-releasing hormone antagonist protocol in infertile women with normal ovarian reserve: an open-label, randomized controlled trial.

This study aimed to evaluate the cumulative live birth rate (cLBR) of progestin-primed ovarian stimulation (PPOS) protocol versus gonadotropin-releasing hormone antagonist (GnRH-ant) protocol for in vitro fertilization (IVF) cycle in infertile women with normal ovarian reserve (NOR). Infertile women with NOR who underwent their first IVF cycle were enrolled in an open-label randomized controlled trial. Patients were randomly assigned 1:1 to receive a freeze-all strategy with delayed embryo transfer (PPOS group, n = 174) and fresh embryo transfer first (GnRH-ant group, n = 174). The primary outcome was the cLBR per aspiration. The cLBR between the PPOS group and GnRH-ant group were comparable (55.75% vs. 52.87%, p = 0.591). A premature luteinizing hormone surge was not observed in the PPOS group, while there were six cases (3.45%) in the GnRH-ant group, but no premature ovulation in either of the groups. The pregnancy outcomes, including implantation rate, clinical pregnancy rate and miscarriage rate, were all comparable. In addition, the number of retrieved oocytes, mature oocytes and viable embryos were similar (all p > 0.05) between the two groups.

Low-dose radiation from CT examination induces DNA double-strand breaks and detectable changes of DNA methylation in peripheral blood cells.

BACKGROUND: Radiation burden from CT examinations increases rapidly with the increased clinical use frequency. Previous studies have disclosed the association between radiation exposure and increased double-strand breaks (DSBs) and changes in DNA methylation. However, whether the induced DSBs by CT examination recover within 24h and whether a CT examination induces detectable gene-specific methylation changes are still unclear. The aim of the present study was to analyze γ-H2AX in the peripheral blood lymphocyte (PBL) of healthy adults before and after CT examination and to discover the differentially methylated positions (DMPs) along with an analysis of DNA methylation changes caused by CT examination. MATERIALS AND METHODS: Peripheral blood samples of 4 ml were drawn from 20 healthy volunteers at three time points: before CT examination, after CT examination 1h, and after CT examination 24h. γ-H2AX immunofluorescence and Illumina Infinium Human Methylation EPIC BeadChip (850k BeadChip) were used respectively for the test of DSBs and the epigenome-wide DNA methylation analysis. Linear mixed-effect (LME) models were used to evaluate the impacts of doses represented by different parameters and foci on genome-wide DNA methylation. RESULTS: The number of γ-H2AX foci per cell at 1h showed linear dose-responses for the radiation doses represented by CT index volume (CTDIvol), dose length product (DLP), and blood absorbed dose, respectively. Residual γ-H2AX foci was observed after CT examination at 24h (p < .001). DMPs and γ-H2AX foci changes could be found within 1h. One CpG site related to PAX5 was significantly changed by using most of the parameters in LME models and did not recover till 24h. CONCLUSIONS: Residual γ-H2AX foci exist after CT examination at 24h. The DNA methylation changes induced by CT examination may not recover within 24h. The DNA methylation had been changed as early as at 1h. The PAX5-related CpG site may be a potential biomarker of low-dose radiation. CLINICAL RELEVANCE: The biological effects and the cancer risks of CT examination are still unclear. The present study is an effort to document the CT scan-induced events in 24h in vivo. The CT scanning area should be strictly limited, and non-essential repeated operations shouldn't be performed within 24h.

Chinese Clinical Trial Registry 13-year data collection and analysis: geographic distribution, financial support, research phase, duration, and disease categories.

Objective: To evaluate the current status of trial registration on the Chinese Clinical Trial Registry (ChiCTR). Design: In this descriptive study, a multi-dimensional grouping analysis was conducted to estimate trends in the annual trial registration, geographical distribution, sources of funding, targeted diseases, and trial subtypes. Setting: We have analyzed all clinical trial records (over 30,000) registered on the Chinese Clinical Trial Registry (ChiCTR) from 2007 to 2020 executed in China. Main outcomes and measures: The main outcome was the baseline characteristics of registered trials. These trials were categorized and analyzed based on geographical distribution, year of implementation, disease type, resource and funding type, trial duration, trial phase, and the type of experimental approach. Results: From 2008 to 2017, a consistent upward trend in clinical trial registrations was observed, showing an average annual growth rate of 29.2%. The most significant year-on-year (yoy%) growth in registrations occurred in 2014 (62%) and 2018 (68.5%). Public funding represented the predominant source of funding in the Chinese healthcare system. The top five ChiCTR registration sites for all disease types were highly populated urban regions of China, including Shanghai (5,658 trials, 18%), Beijing (5,127 trials, 16%), Guangdong (3,612 trials, 11%), Sichuan (2,448 trials, 8%), and Jiangsu (2,196 trials, 7%). Trials targeting neoplastic diseases accounted for the largest portion of registrations, followed by cardio/cerebrovascular disease (CCVD) and orthopedic diseases-related trials. The largest proportions of registration trial duration were 1-2 years, less than 1 year, and 2-3 years (at 27.36, 26.71, and 22.46%). In the case of the research phase, the top three types of all the registered trials are exploratory research, post-marketing drugs, and clinical trials of new therapeutic technology. Conclusion and relevance: Oncological and cardiovascular diseases receive the highest share of national public funding for medical clinical trial-based research in China. Publicly funded trials represent a major segment of the ChiCTR registry, indicating the dominating role of public governance in this health research sector. Furthermore, the growing number of analyzed records reflect the escalation of clinical research activities in China. The tendency to distribute funding resources toward exceedingly populated areas with the highest incidence of oncological and cardiovascular diseases reveals an aim to reduce the dominating disease burden in the urban conglomerates in China.

Good performance of syphilis rapid diagnostic test kits among young key populations in Thailand.

BACKGROUND: The prevalence of syphilis is increasing among adolescents and young adults (AYAs) globally. Use of syphilis rapid diagnostic treponemal tests (RDTs) may improve test coverage and same-day treatment. This study aims to determine sensitivity and specificity of two syphilis RDTs. METHODS: A cross-sectional study was conducted in men who have sex with men and transgender women aged 15-24 years attending a sexual health clinic in Bangkok. Syphilis RDTs used were Determine Syphilis TP and Bioline Syphilis 3.0, using whole blood from finger pricks and venipuncture. Treponemal pallidum electrochemiluminescence assay was used as standard reference. RESULTS: From February to July 2022, 200 AYAs with a mean age 21.1 (SD2.1) years were enrolled, including 50 (25.0%) living with HIV. Prevalence of syphilis was 10.5% (95%CI 6.6-15.6), which was higher among AYAs living with HIV (22.0%) compared with AYAs unaffected by HIV (6.7%). Sensitivities of Determine Syphilis TP and Bioline Syphilis 3.0 were 85.7% (95%CI 63.7-97.0) and 66.7% (95%CI 43.0-85.4), respectively. Specificity of both RDTs was 100% (95%CI 98.0-100.0). Performance of RDTs was similar for both specimens. CONCLUSIONS: Syphilis RDTs have high sensitivity and specificity in diagnosing syphilis. It should be considered for use in sexual health clinics with high syphilis prevalence to initiate treatment promptly.

Publication of studies registered in Clinical Trials Registry of India: An audit of mood disorder research protocols from 2009-2019.

Background: Selective publication of studies has important scientific, ethical, and public health implications. Aim: We studied selective publication among mood disorder research protocols registered in the Clinical Trials Registry of India (CTRI) database. We also examined the frequency and nature of protocol deviations among the published articles. Methods: Using a systematic search strategy, we examined the publication status of all mood disorder-related research protocols registered in the CTRI database from inception till December 31, 2019. Logistic regression analysis was used to identify variables associated with selective publication. Results: Of 129 eligible protocols identified, only a third (n = 43, 33.3%) were published in literature; among those published, only 28 (21.7%) were placed in MEDLINE indexed journals. Protocol deviations were observed in more than half of the published papers (n = 25, 58.1%); many of these (41.9%) were related to sample size deviations, though, importantly, deviations in primary and secondary outcomes were also noted (16.2%). Retrospective registration of trials (odds ratio, 2.98, 95% confidence interval, 1.32-6.71) was significantly associated with publication; other variables, such as funding status or multicentric sampling, were not associated with eventual publication. Conclusions: Two out of three mood disorder research protocols registered in India do not translate into published research. These findings from a low- and middle-income country with limited spending on health care research and development represent wastage of resources and raise scientific and ethical concerns about unpublished data and futile patient participation in research.

Need to reinvigorateTuberculosis research in India - A review of studies registered under clinical trial registry of India.

Tuberculosis (TB) is one of the most serious public health issues in India. According to the global TB report 2020, India accounts for about one-quarter of the global TB burden. Despite considerable advances in mandatory notification of all TB cases, incorporation of the national health programmes with general health services (National Health Mission), and national drug resistance surveillance and many other accomplishments, much more needs to be considered in India to significantly decrease TB incidence. Research is the foundation for medical breakthroughs. In this study, all Tuberculosis-related studies registered under Clinical Trial Registry of India from its inception in July 2007 to February 2021 were reviewed and analysed using the keyword ''Tuberculosis'' in the 'Trial Search' section. A total of 31,196 studies were registered in CTRI, with 180 studies (0.58%) being related to tuberculosis. Of these studies, 76 (42.2%) were interventional in nature. These consisted of evaluating different management or treatment TB (50%, n = 90), diagnostic studies (19.4%, n = 35) and studies related to screening and prevention of TB (7.8%, n = 14). Maximum studies were conducted to evaluate safety and efficacy of anti-TB drugs (10%, n = 18) and to evaluate efficacy of shortening of duration of treatment (8.9%, n = 16). The studies related to extra pulmonary TB, MDR TB and TB in special populations and sources of funding and locations of the study sites were also analysed. These indicate that only minimal TB-related researches are conducted in India. It is indispensable to promote tuberculosis research in India in order to eradicate this infectious disease.

Adjusting for publication bias in meta-analysis via inverse probability weighting using clinical trial registries.

Publication bias is a major concern in conducting systematic reviews and meta-analyses. Various sensitivity analysis or bias-correction methods have been developed based on selection models, and they have some advantages over the widely used trim-and-fill bias-correction method. However, likelihood methods based on selection models may have difficulty in obtaining precise estimates and reasonable confidence intervals, or require a rather complicated sensitivity analysis process. Herein, we develop a simple publication bias adjustment method by utilizing the information on conducted but still unpublished trials from clinical trial registries. We introduce an estimating equation for parameter estimation in the selection function by regarding the publication bias issue as a missing data problem under the missing not at random assumption. With the estimated selection function, we introduce the inverse probability weighting (IPW) method to estimate the overall mean across studies. Furthermore, the IPW versions of heterogeneity measures such as the between-study variance and the I2 measure are proposed. We propose methods to construct confidence intervals based on asymptotic normal approximation as well as on parametric bootstrap. Through numerical experiments, we observed that the estimators successfully eliminated bias, and the confidence intervals had empirical coverage probabilities close to the nominal level. On the other hand, the confidence interval based on asymptotic normal approximation is much wider in some scenarios than the bootstrap confidence interval. Therefore, the latter is recommended for practical use.

Rotavirus vaccine clinical trials: a cross-sectional analysis of clinical trials registries.

BACKGROUND: Rotavirus is a primary infectious virus causing childhood diarrhoea and is associated with significant mortality in children. Three African countries (Nigeria, the Democratic Republic of Congo, and Angola) are among the five countries that account for 50% of all diarrheal-related deaths worldwide. This indicates that much needs to be done to reduce this burden. The World Health Organization International Clinical Trial Registry Platform (WHO ICTRP) is a global repository for primary registries reporting on clinical trials. This study aimed to identify and describe planned, ongoing, and completed rotavirus vaccine trials conducted globally. METHODS: We searched WHO-ICTRP on 17 June 2021 and conducted a cross-sectional analysis of rotavirus studies listed in the database. Data extraction included trial location, participant age, source of the trial record, trial phase, sponsor, and availability of results. We used the Microsoft Excel 365 package to generate descriptive summary statistics. RESULTS: We identified 242 rotavirus vaccine trials registered from 2004 to 2020. Most of these trials were registered retrospectively, with only 26% of the rotavirus vaccine trials reporting the availability of results in their registries. Most of the trials are studying children aged less than 5 years. The recruitment status for these trials is currently shown in the WHO-ICTRP as "not recruiting" for 80.17% of trials, "recruiting" for 11.57% of trials recruiting, and unknown for 6.61% of trials. The continents in which these rotavirus vaccine trials have recruitment sites in Asia (41%) and North America (20%), with the maximum number of trials in the clinical trial registries coming from India (21%) and the USA (11%) with most being sponsored by the pharmaceutical industry. Our analysis shows that only 26% of the rotavirus vaccine trials report the availability of results in their registries. CONCLUSIONS: Mapping rotavirus vaccine clinical trial activity using data from the WHO ICTRP beneficial provides valuable information on planned, ongoing, or completed trials for researchers, funders, and healthcare decision-makers. Despite the high rotavirus disease burden in low- and middle-income countries, including Africa, there is minimal clinical trial activity related to the condition on the continent. The clinical trial registries as a valuable tool to share interim results of the trials.

Clinical trials in Bosnia and Herzegovina: Challenges and future perspectives.

Background: Clinical trials (CTs) are research investigations in which participants receive medical treatments, interventions, or tests to assess their safety and efficacy. Each planned clinical is registered through local or national medical agencies, which may differ in the amount of administrative and legal procedures. The objective of this study was to systematically analyze the registration process for clinical trials in Bosnia and Herzegovina in comparison to other Balkan countries. Methods: The search strategy was based using two online databases: Clinicaltrials.gov (CTGR) and Cortellis Clinical Trials Intelligence (cTi). Search engines included studies until 26th April 2021 and countries were compared in terms of the number of studies, status, type, funding, clinical phases and demographic data. Results: The total number of clinical trials from Bosnia and Herzegovina recorded in the CTGR database was 219, while the cTi database comprised 254 registered studies. The total number of reported clinical trials in CTGR and cTi databases were highest in Serbia (n = 1229, n = 1438), followed by Croatia (n = 1142, n = 1300), and Slovenia (n = 801, n = 948), respectively. However, the highest number of clinical trials per capita is in Slovenia (3.85e-4 in CTGR; 4.56e-4 in cTi), followed by Croatia (2.78e-4 in CTGR; 3.17e-4 in cTi), Serbia (1.41e-4 in CTGR; 1.65e-4 in cTi), and Bosnia and Herzegovina (0.67e-4 CTGR; 0.78e-4 cTi). Conclusion: Our analysis showed that Bosnia has the lowest number of clinical trials in the Balkans. Furthermore, the registration process is complex and longer than in developed countries. Since the healthcare system has been in a transition in the past decade, clinical trials are underutilized as a tool for the improvement of patient care. The clinical trial registration process could be improved by establishing an ethical committee at the state level and by enabling a parallel submission process to ethical committees and databases.

Effect of melatonin intake on postural balance, functional mobility and fall risk in persons with multiple sclerosis: a pilot study.

AIM: To assess the safety and the effect of a nocturnal melatonin (MEL) ingestion on postural balance, functional mobility and fall risk the following morning in adults with multiple sclerosis (MS). METHODS: Fourteen adults with relapsing-remitting MS (RR-MS) (28.36 ± 6.81 years) were evaluated before and after nocturnal ingestion of MEL (6 mg) or placebo (PLA). Evaluations included a posturographic test of static bipedal postural balance with dual-task in eyes open (EO) and eyes closed conditions, and a clinical test of unipedal balance. The physical performance tests were: Timed Up and Go test (TUGT) (mobility), Four Square Step Test (FSST) (fall risk), and Timed 25-foot walk test (T25FWT) (walking speed). Cognitive performance [Montreal Cognitive Assessment (MoCA) and Simple Reaction Time (SRT) tests] and sleep quality [Spiegel's sleep questionnaire (SSQ)] were also assessed. RESULTS: In EO condition, MEL decreased the posturographic parameters [center of pressure (CoP) sway area (CoPAr), CoP path length (CoPL) and CoPL in the mediolateral axis (CoPLX)] more than PLA by 15.82% (p = 0.0006), 12.48% (p = 0.0004) and 14.25% (p = 0.0002), respectively. Durations of TUGT and FSST decreased following MEL session more than the PLA one by 14.52% (p = 0.017) and 19.85% (p = 0.0006), respectively. MEL increased the unipedal stance time, SSQ and MoCA scores more than PLA by 49.81% (p = 0.04), 32.21% (p = 0.004) and 11.87% (p = 0.008), respectively. CONCLUSION: This pilot study showed that acute nocturnal MEL ingestion seems to be safe for enhancing postural balance, fun mobility and fall risk in RR-MS adults probably through improving sleep quality and cognitive function.

Restoration of the gut microbiota is associated with a decreased risk of hepatic encephalopathy after TIPS.

Background & Aims: Hepatic encephalopathy (HE) is a major complication after transjugular intrahepatic portosystemic shunt (TIPS) and is primarily influenced by the gut microbiota. We aimed to evaluate alterations in the microbiota after TIPS and the association between such alterations and HE. Methods: We conducted a prospective longitudinal study of 106 patients with cirrhosis receiving TIPS. Faecal samples were collected before and after TIPS, and the gut microbiota was analysed by 16S ribosomal RNA sequencing. Results: Among all patients, 33 developed HE (HE+ group) within 6 months after TIPS and 73 did not (HE- group), and 18 died during follow-up. After TIPS, the autochthonous taxa increased, whereas the potential pathogenic taxa decreased in the HE- group, and the autochthonous taxon Lachnospiraceae decreased in the HE+ group. Furthermore, synergism among harmful bacteria was observed in all patients, which was weakened in the HE- group (p <0.001) but enhanced in the HE+ group (p <0.01) after TIPS. Variations of 5 autochthonous taxa, namely, Coprococcus, Ruminococcus, Blautia, Ruminococcaceae_uncultured, and Roseburia, were negatively correlated with the severity of HE. Notably, increased abundances of Coprococcus and Ruminococcus were protective factors against HE, and the incidences of HE in patients with improved, stable, and deteriorated microbiota after TIPS were 13.3, 25.9, and 68.2%, respectively. Higher total bilirubin level, Child-Pugh score, model for end-stage liver disease score, Granulicatella, and Alistipes and lower Subdoligranulum before TIPS were the independent risk factors for death. Conclusions: Alterations in gut dysbiosis were negatively related to the occurrence and severity of post-TIPS HE, and the pre-TIPS microbiota were associated with death, suggesting the gut microbiota could be a promising potential biological target for screening suitable patients receiving TIPS and prevention and treatment of post-TIPS HE. Lay summary: Alterations in the gut microbiota after transjugular intrahepatic portosystemic shunt (TIPS) and the relationship between such alterations and post-TIPS hepatic encephalopathy (HE) remain unclear. We therefore performed this study and found that after TIPS, restoration of the gut microbiota, mainly characterised by expansion of autochthonous taxa, depletion of harmful taxa, and weakening of synergism among harmful bacteria, was inversely related to the occurrence and severity of post-TIPS HE.

Registration of intervention trials of Traditional Chinese Medicine for four neurological diseases on Chinese Clinical Trial Registry and ClinicalTrials.gov: a narrative review.

OBJECTIVE: To analyze the current status of clinical trial registration of Traditional Chinese Medicine (TCM) for the treatment of neurological diseases. METHODS: Interventional clinical trials of TCM treatment for ischemic stroke, hemorrhagic stroke, vascular cognitive impairment, tension-type headache before September 22, 2020 on the platform of Chinese Clinical Trial Registry (ChiCTR), and ClinicalTrials.gov were searched. Two researchers independently selected the literature and extracted data. RESULTS: A total of 180 interventional clinical trials were included for analysis. Out of 180 trials, 127 were from ChiCTR and 53 from ClinicalTrials.gov. The countries primary sponsoring the included trials were China (176, 97.8%), and the common categories of primary sponsors were hospital (131, 72.8%). Among the study design, the largest proportion of allocation was randomized (172, 95.6%), interventional model assignment was parallel (163, 90.6%), masking was double blind 49 (27.2%), and the sample size was ≤ 400 (144, 80.0%). The trials were most carried out at a single center (102, 56.7%). Among the included studies, 112 (62.2%) registered on ChiCTR attached the ethical approval documents. In terms of trial stages, 50 (27.7%) studies were in phase IV. The mostly used intervention was Chinese herbal medicines (99, 55%), acupuncture (68, 37.8%) was the second. By searching the registration number on China National Knowledge Infrastructure Database and PubMed, 38 (21.1%) registered trials were published, including 25 protocol studies and 14 research results with one (NCT02275949) published both the protocol and the results. CONCLUSIONS: Irregular and inadequate reporting, untimely update and publication, insufficient information on traditional medicine unique characteristics, and lack of international collaborations are the problems existing in the interventional clinical registration trials of traditional medicine treatment on neurological diseases. More efforts need to be made from the above aspects to standardize and improve the registration of traditional medicine trials.

Agreement of primary outcomes in chiropractic-related clinical trials registered in clinicaltrials.gov with corresponding publication.

INTRODUCTION: Previous analysis of registered clinical trials has found a number of protocols result in changes in the registered primary outcome measures. This investigation determined if reported primary outcomes in chiropractic-related clinical trials registered in clinicaltrials.gov match their published results. Additionally, we assessed secondary outcomes, publication status and whether raw data were posted to the registry. METHODS: Clinicaltrials.gov was searched for chiropractic-related trials and having a completed status. If the study was published, outcome measures were compared between the clinicaltrials.gov entry and the published paper to assess for consistency. RESULTS: Within clinicaltrials.gov 171 chiropracticrelated protocols were identified with 102 of those published (59.6% publication rate). Ninety-two of the published papers (90.2%) had agreement between their primary outcome and the entry on clinicaltrials.gov and 82 (80.4%) agreed with the secondary outcomes. CONCLUSION: A modest rate of agreement between clinicaltrials.gov entries and the published papers was found. While chiropractic-related clinical trials are fewer compared to medical trials, chiropractic-related research has a substantially better rate of primary and secondary outcome concordance with registered protocols.

INTRODUCTION: En examinant des essais cliniques enregistrés, on s'est rendu compte qu'un certain nombre de protocoles faisaient varier les résultats principaux. On a mené une étude pour savoir si les résultats primaires d'essais cliniques sur la chiropratique enregistrés sur clinicaltrials.gov correspondaient à ceux publiés. On a aussi examiné les résultats secondaires, l'état de publication et cherché à savoir si les données brutes étaient publiées dans le registre. MÉTHODOLOGIE: Dans la base de données Clinicaltrials.gov, on a repéré des essais cliniques sur la chiropratique qui étaient terminés. Lorsque l'essai clinique avait été publié, on a comparé les résultats au moment de son enregistrement sur clinicaltrials.gov à ceux parus dans des publications pour savoir s'ils concordaient. RÉSULTATS: Sur le site clinicaltrials.gov, on a trouvé 171 études sur la chiropratique, dont 102 avaient été publiés (taux de publication:59,6 %). Pour quatrevingt-douze publications (90,2 %), on a observé une concordance entre les résultats primaires au moment de l'enregistrement sur clinicaltrials.gov et 82 (80,4 %) et les résultats secondaires. CONCLUSION: On a observé un taux modeste de concordance entre les données à l'enregistrement sur clinicaltrails.gov et les données publiées. Les essais cliniques sur la chiropratique sont moins nombreux que des essais cliniques de médicaments. Mais le taux de concordance entre les résultats primaires et les résultats secondaires était considérablement plus élevé lorsque les protocoles de recherches sur la chiropratique sont enregistrés.

Using clinical trial registries to inform Copas selection model for publication bias in meta-analysis.

Prospective registration of study protocols in clinical trial registries is a useful way to minimize the risk of publication bias in meta-analysis, and several clinical trial registries are available nowadays. However, they are mainly used as a tool for searching studies and information submitted to the registries has not been utilized as efficiently as it could. In addressing publication bias in meta-analyses, sensitivity analysis with the Copas selection model is a more objective alternative to widely-used graphical methods such as the funnel-plot and the trim-and-fill method. Despite its ability to quantify the potential impact of publication bias, the Copas selection model relies on sensitivity analyses, in which some parameters are varied across a certain range. This may result in some difficulty in interpreting the results. In this paper, we propose an alternative inference procedure for the Copas selection model by utilizing information from clinical trial registries. Our method provides a simple and accurate way to estimate all unknown parameters of the Copas selection model. A simulation study revealed that our proposed method resulted in smaller biases and more accurate confidence intervals than existing methods. Furthermore, three published meta-analyses were re-analyzed to demonstrate how to implement the proposed method in practice.

Characteristics of Asian 4 countries on cancer clinical trials registered in the International Clinical Trials Registry Platform between 2005 and 2018.

BACKGROUND: The characteristics and comparison of countries regarding clinical trials for cancer were unknown. The World Health Organization-International Clinical Trials Registry Platform (WHO-ICTRP) are providing data from various countries and releases them generally in a downloadable format. We aimed to examine and descriptively identify the number of cancer clinical trials registered in the world and the fundamental characteristics in Asian 4 countries of China, India, Japan and South Korea, focusing on study characteristics, e.g., phase or targeted size, using the WHO-ICTRP. METHODS: We extracted information on cancer clinical studies in the ICTRP database on September 20, 2019. Then, we performed a cross-sectional study on the annual number of registered studies and country, registered registry, phase, target sizes and sponsors. RESULTS: We identified 80,677 cancer clinical studies. The annual number of registered cancer clinical studies significantly increased between 2005 and 2018 (3,172 to 8,156, ß =382.2, 95% CI: 329.6, 434.8). Among the Asian 4 countries, the numbers of trials were significantly increasing in 2005-2018 (P<0.001). The characteristics on interventional studies for cancer differed in those 4 countries, e.g., the registered registries, phase and sponsors, compared with the US. CONCLUSIONS: This study descriptively clarified an increase and the characteristics of cancer clinical trials in Asian 4 countries. It suggests to take that characteristics into account and select a database or data source discreetly for analysis of clinical trials, according to the purpose of the research and the required data.

Clinical studies of traditional Japanese herbal medicines (Kampo): Need for evidence by the modern scientific methodology.

BACKGROUND: Japanese Kampo medicine is a traditional medicine with roots in ancient Chinese medicine. Because traditional physicians had been abolished in Japan, the present mainstream of Kampo treatment is that physicians who learned modern Western medicine prescribe Kampo extract products based on Western medical diagnosis. This situation is different from that in other east Asian countries, and the physicians require scientific clinical evidence. METHODS: Clinical studies were searched from literature databases, clinical trial registry sites, and "Evidence Reports of Kampo Treatment (EKAT)" published by the Japan Society for Oriental Medicine. RESULTS: At the approval of Kampo products, scientific clinical evidence was not required because they have a long-period experience as a decoction. However, in the 1990s, Kampo products became a subject for national reevaluation; double-blind and placebo-controlled clinical trials. At the time, a methodological foundation for conducting clinical assessments of Kampo medicines was established. From 2000 onwards, with the evidence-based medicine era, the field of Kampo medicine also saw many randomized controlled trials, and their evidence was collected and published as EKAT. In the 2010s, post-marketing clinical trials of Kampo products also had to be conducted in this environment due to the need for ethical and scientific assurance. Currently, there are numerous clinical trials of Kampo products being conducted with high-grade trial designs. CONCLUSION: The situation of Kampo clinical studies reflects the unique history and position of Kampo medical system and Kampo products in Japan.